36

NSAIDs, Acetaminophen,
&Drugs Used in
Rheumatoid Arthritis
&Gout

Inflammation is a complex response to cell injury that primarily

occurs in vascularized connective tissue and often involves the
immune response. The mediators of inflammation function
to eliminate the cause of cell injury and clear away debris, in
preparation for tissue repair. Unfortunately, inflammation also
causes pain and, in instances in which the cause of cell injury
is not eliminated, can result in a chronic condition of pain
and tissue damage such as that seen in rheumatoid arthritis.
The nonsteroidal anti-inflammatory drugs (NSAIDs) and

318

High-Yield Terms to Learn

acetaminophen are often effective in controlling inflammatory

pain. Other treatment strategies applied to the reduction of
inflammation are targeted at immune processes. These include
glucocorticoids and disease-modifying antirheumatic drugs
(DMARDs). Gout is an inflammatory joint disease caused by
precipitation of uric acid crystals. Treatment of acute episodes
targets inflammation, whereas treatment of chronic gout targets
both inflammatory processes and the production and elimination of uric acid.

Anti-inflammatory drugs, acetaminophen,

drugs used in gout

Anti-inflammatory
drugs

NSAIDs

Aspirin

Other
nonselective
NSAIDs

Acetaminophen

DMARDs

COX-2
O
inhibitors
(celecoxib)

Drugs used
in gout

Acute

PART VI Drugs with Important Actions on Blood, Inflammation, & Gout

Chronic

Antipyretic

A drug that reduces fever (eg, aspirin, NSAIDs, acetaminophen)

Cyclooxygenase (COX)

The enzyme at the head of the enzymatic pathway for prostaglandin synthesis (Figure 36-2)

Cytotoxic drug

Drugs that interfere with essential metabolic processes, especially DNA maintenance
and replication and cell division. Such drugs generally kill rapidly dividing cells and are
used for cancer chemotherapy and immunosuppression (Chapters 54 and 55)

Disease-modifying antirheumatic
drugs (DMARDs)

Diverse group of drugs that modify the inflammatory processes underlying rheumatoid
arthritis; they have a slow (weeks to months) onset of clinical effects

Nonsteroidal anti-inflammatory
drugs (NSAIDs)

Inhibitors of cyclooxygenase; the term nonsteroidal differentiates them from steroid

drugs that mediate anti-inflammatory effects through activation of glucocorticoid
receptors (eg, cortisol; Chapter 39)

Reyes syndrome

A rare syndrome of rapid liver degeneration and encephalitis in children treated with
aspirin during a viral infection

Tumor necrosis factor-` (TNF-`)

A cytokine that plays a central role in inflammation

Uricosuric agent

A drug that increases the renal excretion of uric acid

Xanthine oxidase

A key enzyme in the purine metabolism pathway that converts hypoxanthine to

xanthine and xanthine to uric acid

ASPIRIN & OTHER

NONSELECTIVE NSAIDs

TABLE 361 Selected NSAIDs.

Drug

A. Classification and Prototypes

Aspirin

Aspirin (acetylsalicylic acid) is the prototype of the salicylates

and other NSAIDs (Table 361). The other older nonselective
NSAIDs (ibuprofen, indomethacin, many others) vary primarily
in their potency, analgesic and anti-inflammatory effectiveness,
and duration of action. Ibuprofen and naproxen have moderate effectiveness; indomethacin has greater anti-inflammatory
effectiveness; and ketorolac has greater analgesic effectiveness.
Celecoxib was the first member of a newer NSAID subgroup, the
cyclooxygenase-2 (COX-2)-selective inhibitors, which were developed in an attempt to lessen the gastrointestinal toxicity associated
with COX inhibition while preserving efficacy. Unfortunately,
clinical trials involving some of the highly selective COX-2 inhibitors have shown a higher incidence of cardiovascular thrombotic
events than the nonselective drugs.

Glucocorticoids

Colchicine

Uricosurics
(probenecid)

Xanthine oxidase
inhibitors (allopurinol)

As noted in Chapter 18, cyclooxygenase is the enzyme that converts arachidonic acid into the endoperoxide precursors of prostaglandins, important mediators of inflammation (Figure 361).
Cyclooxygenase has at least 2 isoforms: COX-1 and COX-2.
COX-1 is primarily expressed in noninflammatory cells, whereas
COX-2 is expressed in activated lymphocytes, polymorphonuclear
cells, and other inflammatory cells.
Aspirin and nonselective NSAIDs inhibit both cyclooxygenase
isoforms and thereby decrease prostaglandin and thromboxane
synthesis throughout the body. Release of prostaglandins necessary
for homeostatic function is disrupted, as is release of prostaglandins involved in inflammation. The COX-2-selective inhibitors
317

0.25

Celecoxib

11

Diclofenac

1.1

Diflunisal

13

Etodolac

6.5

Fenoprofen

2.5

Flurbiprofen

3.8

Ibuprofen
Indomethacin
Ketoprofen
Ketorolac

B. Mechanism of Action
NSAIDs

Half-life (hours)

2
45
1.8
410

Meloxicam

20

Nabumetonea

26

Naproxen

14

Oxaprozin

58

Piroxicam

57

Sulindac

Tolmetin

Nabumetone is a prodrug; the half-life is for its active metabolite.

(Modified and reproduced, with permission, from Katzung BG, editors: Basic & Clinical
Pharmacology, 11th ed. McGraw-Hill, 2009.)

CHAPTER 36 NSAIDs, Acetaminophen, &Drugs Used in Rheumatoid Arthritis &Gout

319

Stimulus

Disturbance of cell membranes

Phospholipids
Phospholipase inhibitors
Corticosteroids

Lipoxygenase

Cyclooxygenase

NSAID, ASA

Leukotrienes

LTB4

LTC4/D4/E4

Phagocyte
attraction,
activation

Alteration of vascular
permeability, bronchial
constriction, increased
secretion

Prostaglandins

Thromboxane

Inflammation

Bronchospasm,
congestion,
mucous plugging

Leukocyte modulation

Inflammation

Prostanoid mediators derived from arachidonic acid and sites of drug action. ASA, acetylsalicylic acid (aspirin);
LT, leukotriene; NSAID, nonsteroidal anti-inflammatory drug. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical
Pharmacology, 12thed. McGraw-Hill, 2012: Fig. 362.)

C. Effects
Arachidonic acid derivatives are important mediators of inflammation; cyclooxygenase inhibitors reduce the manifestations of
inflammation, although they have no effect on underlying tissue
damage or immunologic reactions. These inhibitors also suppress the prostaglandin synthesis in the CNS that is stimulated
by pyrogens and thereby reduces fever (antipyretic action). The
analgesic mechanism of these agents is less well understood.
Activation of peripheral pain sensors may be diminished as a

2. Other NSAIDsThe other NSAIDs are well absorbed after

oral administration. Ibuprofen has a half-life of about 2 h, is
relatively safe, and is the least expensive of the older, nonselective NSAIDs. Naproxen and piroxicam are noteworthy because
of their longer half-lives (Table 361), which permit less frequent dosing. These other NSAIDs are used for the treatment
of mild to moderate pain, especially the pain of musculoskeletal
inflammation such as that seen in arthritis and gout. They are
also used to treat many other conditions, including dysmenorrhea, headache, and patent ductus arteriosus in premature
infants. Ketorolac is notable as a drug used mainly as a systemic
analgesic, not as an anti-inflammatory (although it has typical
nonselective NSAID properties). It is the only NSAID available in a parenteral formulation. Nonselective NSAIDs reduce
polyp formation in patients with primary familial adenomatous
polyposis. Long-term use of NSAIDs reduces the risk of colon
cancer.

E. Toxicity

FIGURE 361

have less effect on the prostaglandins involved in homeostatic

function, particularly those in the gastrointestinal tract.
The major difference between the mechanisms of action
of aspirin and other NSAIDs is that aspirin (but not its active
metabolite, salicylate) acetylates and thereby irreversibly inhibits cyclooxygenase, whereas the inhibition produced by other
NSAIDs is reversible. The irreversible action of aspirin results in a
longer duration of its antiplatelet effect and is the basis for its use
as an antiplatelet drug (Chapter 34).

PART VI Drugs with Important Actions on Blood, Inflammation, & Gout

Prostacyclin

Colchicine

Receptor
antagonists

Arachidonic acid

Lipoxygenase inhibitors

Phospholipase A2

Fatty acid substitution (diet)

320

result of reduced production of prostaglandins in injured tissue;

in addition, a central mechanism is operative. Cyclooxygenase
inhibitors also interfere with the homeostatic function of prostaglandins. Most important, they reduce prostaglandin-mediated
cytoprotection in the gastrointestinal tract and autoregulation of
renal function.

D. Pharmacokinetics and Clinical Use

1. AspirinAspirin has 3 therapeutic dose ranges: The low
range (<300 mg/d) is effective in reducing platelet aggregation; intermediate doses (3002400 mg/d) have antipyretic and
analgesic effects; and high doses (24004000 mg/d) are used
for an anti-inflammatory effect. Aspirin is readily absorbed and
is hydrolyzed in blood and tissues to acetate and salicylic acid.
Salicylate is a reversible nonselective inhibitor of cyclooxygenase.
Elimination of salicylate is first order at low doses, with a
half-life of 35 h. At high (anti-inflammatory) doses, half-life
increases to 15 h or more and elimination becomes zero order.
Excretion is via the kidney.

1. AspirinThe most common adverse effect from

therapeutic anti-inflammatory doses of aspirin is gastric upset.
Chronic use can result in gastric ulceration, upper gastrointestinal bleeding, and renal effects, including acute failure
and interstitial nephritis. Aspirin increases the bleeding time
(Chapter 34). When prostaglandin synthesis is inhibited by
even small doses of aspirin, persons with aspirin hypersensitivity (especially associated with nasal polyps) can experience
asthma from the increased synthesis of leukotrienes. This type
of hypersensitivity to aspirin precludes treatment with any
NSAID. At higher doses of aspirin, tinnitus, vertigo, hyperventilation, and respiratory alkalosis are observed. At very
high doses, the drug causes metabolic acidosis, dehydration,
hyperthermia, collapse, coma, and death. Children with viral
infections who are treated with aspirin have an increased risk
for developing Reyes syndrome, a rare but serious syndrome
of rapid liver degeneration and encephalopathy. There is no
specific antidote for aspirin.
2. Nonselective NSAIDsLike aspirin, these agents are
associated with significant gastrointestinal disturbance, but the
incidence is lower than with aspirin. There is a risk of renal
damage with any of the NSAIDs, especially in patients with
preexisting renal disease. Because these drugs are cleared by the
kidney, renal damage results in higher, more toxic serum concentrations. Use of parenteral ketorolac is generally restricted
to 72 h because of the risk of gastrointestinal and renal damage
with longer administration. Serious hematologic reactions have
been noted with indomethacin.
3. COX-2-selective inhibitorsThe COX-2-selective inhibitors (celecoxib, rofecoxib, valdecoxib) have a reduced risk of
gastrointestinal effects, including gastric ulcers and serious gastrointestinal bleeding. The COX-2 inhibitors carry the same risk of
renal damage as nonselective COX inhibitors, presumably because

COX-2 contributes to homeostatic renal effects. Clinical trial

data suggest that highly selective COX-2 inhibitors such as
rofecoxib and valdecoxib carry an increased risk of myocardial
infarction and stroke. The increased risk of arterial thrombosis
is believed to be due to the COX-2 inhibitors having a greater
inhibitory effect on endothelial prostacyclin (PGI2) formation
than on platelet TXA2 formation. Prostacyclin promotes vasodilation and inhibits platelet aggregation, whereas TXA2 has the
opposite effects. Several COX-2 inhibitors have been removed
from the market, and the others are now labeled with warnings
about the increased risk of thrombosis.

ACETAMINOPHEN
A. Classification and Prototype
Acetaminophen is the only over-the-counter non-anti-inflammatory
analgesic commonly available in the United States. Phenacetin, a
toxic prodrug that is metabolized to acetaminophen, is still available in some other countries.

B. Mechanism of Action
The mechanism of analgesic action of acetaminophen is unclear.
The drug is only a weak COX-1 and COX-2 inhibitor in peripheral tissues, which accounts for its lack of anti-inflammatory
effect. Evidence suggests that acetaminophen may inhibit a third
enzyme, COX-3, in the CNS.

C. Effects
Acetaminophen is an analgesic and antipyretic agent; it lacks antiinflammatory or antiplatelet effects.

D. Pharmacokinetics and Clinical Use

Acetaminophen is effective for the same indications as intermediatedose aspirin. Acetaminophen is therefore useful as an aspirin
substitute, especially in children with viral infections and in
those with any type of aspirin intolerance. Acetaminophen is well
absorbed orally and metabolized in the liver. Its half-life, which is
23 h in persons with normal hepatic function, is unaffected by
renal disease.

E. Toxicity
In therapeutic dosages, acetaminophen has negligible toxicity in
most persons. However, when taken in overdose or by patients
with severe liver impairment, the drug is a dangerous hepatotoxin.
The mechanism of toxicity involves oxidation to cytotoxic intermediates by phase I cytochrome P450 enzymes. This occurs if
substrates for phase II conjugation reactions (acetate and glucuronide) are lacking (Chapter 4). Prompt administration of acetylcysteine, a sulfhydryl donor, may be lifesaving after an overdose.
People who regularly consume 3 or more alcoholic drinks per day
are at increased risk of acetaminophen-induced hepatotoxicity
(Chapters 4 and 23).

CHAPTER 36 NSAIDs, Acetaminophen, &Drugs Used in Rheumatoid Arthritis &Gout

SKILL KEEPER: OPIOID ANALGESICS AND

ANTAGONISTS (SEE CHAPTER 31)
Although NSAIDs and acetaminophen are extremely useful for
the treatment of mild to moderate pain, adequate control of
more intense pain often requires treatment with an opioid.
1. Name 1 strong, 1 moderate, and 1 weak opioid drug.
2. Briefly describe the most common adverse effects of strong
and moderate opioids.
3. What drug should be administered in the event of an opioid
overdose?
The Skill Keeper Answers appear at the end of the chapter.

DISEASE-MODIFYING ANTIRHEUMATIC
DRUGS (DMARDs)
A. Classification
This heterogeneous group of agents (Table 362) has antiinflammatory actions in several connective tissue diseases. They
are called disease-modifying drugs because some evidence shows
slowing or even reversal of joint damage, an effect never seen with

321

NSAIDs. They are also called slow-acting antirheumatic drugs

because it may take 6 wk to 6 mo for their benefits to become
apparent. Corticosteroids can be considered anti-inflammatory
drugs with an intermediate rate of action (ie, slower than NSAIDs
but faster than other DMARDs). However, the corticosteroids are
too toxic for routine chronic use (Chapter 39) and are reserved for
temporary control of severe exacerbations and long-term use in
patients with severe disease not controlled by other agents.

B. Mechanisms of Action and Effects

The mechanisms of action of most DMARDs in treating
rheumatoid arthritis are poorly understood. Cytotoxic drugs (eg,
methotrexate) probably act by reducing the number of immune
cells available to maintain the inflammatory response; many of
these drugs are also used in the treatment of cancer (Chapter
54). Other drugs appear to interfere with the activity of T lymphocytes (eg, sulfasalazine, hydroxychloroquine, cyclosporine,
leflunomide, mycophenolate mofetil, abatacept), B lymphocytes
(rituximab), or macrophages (gold compounds). In recent years,
immunoglobulin-based biologic agents that inhibit the action of
tumor necrosis factor- (TNF-), including infliximab, adalimumab, and etanercept, have also shown efficacy in rheumatoid
arthritis, as has the recombinant human interleukin-1 receptor
antagonist anakinra. The immunosuppressant effects of these
drugs are discussed in more detail in Chapter 55.

TABLE 362 Some disease-modifying antirheumatic drugs (DMARDs).

Drug

Other Clinical Uses

Infection, exacerbation of COPD, hypersensitivity reactions

Anakinra

Injection-site reaction, infection, neutropenia

Anti-IL-6 drugs
(tocilizumab)

Upper respiratory tract infections, headache, hypertension, and

elevated liver enzymes

Anti-TNF- drugs (infliximab, etanercept,

adalimumab, golimumab, certolizumab)

Inflammatory bowel disease,

other rheumatic disorders

Infection, lymphoma, hepatoxicity, hematologic effects,

hypersensitivity reactions, cardiovascular toxicity

Cyclosporine

Tissue transplantation

Nephrotoxicity, hypertension, liver toxicity

Hydroxychloroquine, chloroquine

PART VI Drugs with Important Actions on Blood, Inflammation, & Gout

C. Pharmacokinetics and Clinical Use

Sulfasalazine, hydroxychloroquine, methotrexate, cyclosporine,
penicillamine, and leflunomide are given orally. Anti-TNF-
drugs are given by injection. Gold compounds are available for
parenteral use (gold sodium thiomalate and aurothioglucose) and
for oral administration (auranofin).
Increasingly, DMARDs, particularly low doses of methotrexate, are initiated fairly early in patients with moderate to severe
rheumatoid arthritis in an attempt to ameliorate disease progression. Some of these drugs are also used in other rheumatic diseases
such as lupus erythematosus, arthritis associated with Sjgrens
syndrome, juvenile rheumatoid arthritis, and ankylosing spondylitis, and in other immunologic disorders (Chapter 55).

D. Toxicity
All DMARDs can cause severe or fatal toxicities. Careful monitoring of patients who take these drugs is mandatory. Their major
adverse effects are listed in Table 362.

DRUGS USED IN GOUT

A. Classification and Prototypes
Gout is associated with increased serum concentrations of uric acid.
Acute attacks involve joint inflammation initiated by precipitation
of uric acid crystals. Treatment strategies include (1) reducing
inflammation during acute attacks (with colchicine, NSAIDs, or
glucocorticoids; Figure 362); (2) accelerating renal excretion of

Toxicity When Used for Rheumatoid Arthritis

Abatacept

Gold compounds

322

Synoviocytes
Colchicine

Enzymes IL-1

Leflunomide

IL-1

Rash, gastrointestinal disturbance, myopathy, neuropathy, ocular

toxicity
Teratogen, hepatotoxicity, gastrointestinal disturbance, skin
reactions

Methotrexate

Anticancer

Nausea, mucosal ulcers, hematotoxicity, hepatotoxicity,

teratogenicity

Penicillamine

Chelating agent

Many adverse effects, including proteinuria, dermatitis,

gastrointestinal disturbance, hematologic abnormalities

Rituximab

Non-Hodgkins lymphoma

Infusion reaction, rash, infection, cardiac toxicity

Sulfasalazine

Inflammatory bowel disease

Rash, gastrointestinal disturbance, dizziness, headache, leukopenia

FIGURE 362

1. MechanismsNSAIDs such as indomethacin are effective

in inhibiting the inflammation of acute gouty arthritis. These
agents act through the reduction of prostaglandin formation
and the inhibition of crystal phagocytosis by macrophages
(Figure 362). Colchicine, a selective inhibitor of microtubule
assembly, reduces leukocyte migration and phagocytosis; the
drug may also reduce production of leukotriene B4 and decrease
free radical formation.
2. EffectsNSAIDs and glucocorticoids reduce the synthesis
of inflammatory mediators in the gouty joint. Because it reacts
with tubulin and interferes with microtubule assembly, colchicine is a general mitotic poison. Tubulin is necessary for normal
cell division, motility, and many other processes.
3. Pharmacokinetics and clinical useAn NSAID or a
glucocorticoid is preferred for the treatment of acute gouty
arthritis. Although colchicine can be used for acute attacks, the
doses required cause significant gastrointestinal disturbance,
particularly diarrhea. Lower doses of colchicine are used to
prevent attacks of gout in patients with a history of multiple
acute attacks. Colchicine is also of value in the management of
familial Mediterranean fever, a disease of unknown cause characterized by fever, hepatitis, peritonitis, pleuritis, arthritis, and,
occasionally, amyloidosis. Indomethacin, some glucocorticoids,
and colchicine are used orally; parenteral preparations of glucocorticoids and colchicine are also available.

PG

C. Uricosuric Agents

PG

MNP

B. Anti-Inflammatory Drugs Used for Gout

4. ToxicityNSAIDs can cause renal damage, and indomethacin can additionally cause bone marrow depression. Short
courses of glucocorticoids can cause behavioral changes and
impaired glucose control. Because colchicine can severely damage the liver and kidney, dosage must be carefully limited and
monitored. Overdose is often fatal.

LTB 4

PMN
PG

Many adverse effects, including diarrhea, dermatitis, hematologic

abnormalities
Antimalarial

Urate
crystal

uric acid with uricosuric drugs (probenecid or sulfinpyrazone);

and (3) reducing (with allopurinol or febuxostat) the conversion of
purines to uric acid by xanthine oxidase (Figure 363).

Indomethacin,
phenylbutazone

Sites of action of some anti-inflammatory drugs

in a gouty joint. Synoviocytes damaged by uric acid crystals release
prostaglandins (PG), interleukins (ILs), and other mediators of
inflammation. Polymorphonuclear leukocytes (PMN), macrophages,
and other inflammatory cells enter the joint and also release
inflammatory substances, including leukotrienes (eg, LTB4), that attract
additional inflammatory cells. Colchicine acts on microtubules in
the inflammatory cells. NSAIDs act on cyclooxygenase-2 (COXII) and
inhibit PG formation in all of the cells of the joint. MNP, mononuclear
phagocytes. (Reproduced, with permission, from Katzung BG, editor:
Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 365.)

1. MechanismNormally, over 90% of the uric acid filtered

by the kidney is reabsorbed in the proximal tubules. Uricosuric
agents (probenecid, sulfinpyrazone) are weak acids that compete with uric acid for reabsorption by the weak acid transport
mechanism in the proximal tubules and thereby increase uric
acid excretion. At low doses, these agents may also compete
with uric acid for secretion by the tubule and occasionally
can elevate, rather than reduce, serum uric acid concentration.
Elevation of uric acid levels by this mechanism occurs with aspirin (another weak acid) over much of its dose range.
2. EffectsUricosuric drugs inhibit the secretion of a large
number of other weak acids (eg, penicillin, methotrexate) in
addition to inhibiting the reabsorption of uric acid.

CHAPTER 36 NSAIDs, Acetaminophen, &Drugs Used in Rheumatoid Arthritis &Gout

323

Alloxanthine,
febuxostat

O
HN 1 6 5
2

N
7
9

Xanthine
oxidase

O
N

HN

O
Xanthine
oxidase

HN

H
N
O

N
H

Hypoxanthine

N
H

N
H

Xanthine

N
H

N
H

Uric acid

FIGURE 363

The action of xanthine oxidase in uric acid synthesis and metabolism of allopurinol. (Modified and reproduced, with
permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2012: Fig. 367.)

3. Pharmacokinetics and clinical useUricosuric drugs are

used orally to treat chronic gout. These drugs are of no value in
acute episodes.
4. ToxicityUricosuric drugs can precipitate an attack of
acute gout during the early phase of their action. This can be
avoided by simultaneously administering colchicine or indomethacin. Because they are sulfonamides, the uricosuric drugs
may share allergenicity with other classes of sulfonamide drugs
(diuretics, antimicrobials, oral hypoglycemic drugs).

D. Xanthine Oxidase Inhibitors

1. MechanismThe production of uric acid can be
reduced by inhibition of xanthine oxidase, the enzyme that
converts hypoxanthine to xanthine and xanthine to uric
acid (Figure 363). Allopurinol is converted to oxypurinol
(alloxanthine) by xanthine oxidase; alloxanthine is an irreversible suicide inhibitor of the enzyme. The newer drug febuxostat is a nonpurine inhibitor of xanthine oxidase that is more
selective than allopurinol and alloxanthine, which inhibit other
enzymes involved in purine and pyrimidine metabolism.
2. EffectsInhibition of xanthine oxidase increases the concentrations of the more soluble hypoxanthine and xanthine and
decreases the concentration of the less soluble uric acid. As a
result, there is less likelihood of precipitation of uric acid crystals in joints and tissues. Clinical trials suggest that febuxostat
is more effective than allopurinol in lowering serum uric acid.
3. Pharmacokinetics and clinical useThe xanthine oxidase inhibitors are given orally in the management of chronic
gout. Like uricosuric agents, these drugs are usually withheld for
12 wk after an acute episode of gouty arthritis and are administered in combination with colchicine or an NSAID to avoid
an acute attack. Allopurinol is also used as an adjunct to cancer
chemotherapy to slow the formation of uric acid from purines
released by the death of large numbers of neoplastic cells.
4. Toxicity and drug interactionsAllopurinol causes
gastrointestinal upset, rash, and rarely, peripheral neuritis,

vasculitis, or bone marrow dysfunction, including aplastic anemia. It inhibits the metabolism of mercaptopurine and azathioprine, drugs that depend on xanthine oxidase for elimination.
Febuxostat can cause liver function abnormalities, headache,
and gastrointestinal upset.

QUESTIONS
1. Among NSAIDs, aspirin is unique because it
(A) Irreversibly inhibits its target enzyme
(B) Prevents episodes of gouty arthritis with long-term use
(C) Reduces fever
(D) Reduces the risk of colon cancer
(E) Selectively inhibits the COX-2 enzyme
2. Which of the following is an analgesic and antipyretic drug
that lacks an anti-inflammatory action?
(A) Acetaminophen
(B) Celecoxib
(C) Colchicine
(D) Indomethacin
(E) Probenecid
3. A 16-year-old girl comes to the emergency department suffering from the effects of an aspirin overdose. Which of the
following syndromes is this patient most likely to exhibit as a
result of this drug overdose?
(A) Bone marrow suppression and possibly aplastic anemia
(B) Fever, hepatic dysfunction, and encephalopathy
(C) Hyperthermia, metabolic acidosis, and coma
(D) Rapid, fulminant hepatic failure
(E) Rash, interstitial nephritis, and acute renal failure
4. Which of the following drugs is most likely to increase serum
concentrations of conventional doses of methotrexate, a weak
acid that is primarily cleared in the urine?
(A) Acetaminophen
(B) Allopurinol
(C) Colchicine
(D) Hydroxychloroquine
(E) Probenecid

324

PART VI Drugs with Important Actions on Blood, Inflammation, & Gout

5. The main advantage of ketorolac over aspirin is that ketorolac

(A) Can be combined more safely with an opioid such as
codeine
(B) Can be obtained as an over-the-counter agent
(C) Does not prolong the bleeding time
(D) Is available in a parenteral formulation that can be
injected intramuscularly or intravenously
(E) Is less likely to cause acute renal failure in patients with
some preexisting degree of renal impairment
6. An 18-month-old boy dies from an accidental overdose of
acetaminophen. Which of the following is the most likely
cause of this patients death?
(A) Arrhythmia
(B) Hemorrhagic stroke
(C) Liver failure
(D) Noncardiogenic pulmonary edema
(E) Ventilatory failure
Questions 7 and 8. A 52-year-old woman presented with intense
pain, warmth, and redness in the first toe on her left foot.
Examination of fluid withdrawn from the inflamed joint revealed
crystals of uric acid.
7. In the treatment of this womans acute attack of gout, a
high dose of colchicine will reduce the pain and inflammation. However, many physicians prefer to treat acute gout
with a corticosteroid or indomethacin because high doses of
colchicine are likely to cause
(A) Behavioral changes that include psychosis
(B) High blood pressure
(C) Rash
(D) Severe diarrhea
(E) Sudden gastrointestinal bleeding
8. Over the next 7 mo, the patient had 2 more attacks of acute
gout. Her serum concentration of uric acid was elevated. The
decision was made to put her on chronic drug therapy to try
to prevent subsequent attacks. Which of the following drugs
could be used to decrease this womans rate of production of
uric acid?
(A) Allopurinol
(B) Aspirin
(C) Colchicine
(D) Hydroxychloroquine
(E) Probenecid
Questions 9 and 10. A 54-year-old woman presented with
signs and symptoms consistent with an early stage of rheumatoid
arthritis. The decision was made to initiate NSAID therapy.
9. Which of the following patient characteristics is the most
compelling reason for avoiding celecoxib in the treatment of
her arthritis?
(A) History of alcohol abuse
(B) History of gout
(C) History of myocardial infarction
(D) History of osteoporosis
(E) History of peptic ulcer disease

10. Although the patients disease was adequately controlled with

an NSAID and methotrexate for some time, her symptoms
began to worsen and radiologic studies of her hands indicated progressive destruction in the joints of several fingers.
Treatment with another second-line agent for rheumatoid
arthritis was considered. Which of the following is a parenterally administered DMARD whose mechanism of antiinflammatory action is antagonism of tumor necrosis factor?
(A) Cyclosporine
(B) Etanercept
(C) Penicillamine
(D) Phenylbutazone
(E) Sulfasalazine

ANSWERS
1. Aspirin differs from other NSAIDs by irreversibly inhibiting
cyclooxygenase. The answer is A.
2. Acetaminophen is the only drug that fits this description.
Indomethacin is a nonselective COX inhibitor and celecoxib is
a COX-2 inhibitor; both have analgesic, antipyretic, and antiinflammatory effects. Colchicine is a drug used for gout that
also has an anti-inflammatory action. Probenecid is a uricosuric
drug that promotes the excretion of uric acid. The answer is A.
3. Salicylate intoxication is associated with metabolic acidosis,
dehydration, and hyperthermia. If these problems are not
corrected, coma and death ensue. The answer is C.
4. Like other weak acids, methotrexate depends on active tubular excretion in the proximal tubule for efficient elimination.
Probenecid competes with methotrexate for binding to the
proximal tubule transporter and thereby decreases the rate of
clearance of methotrexate. The answer is E.
5. Ketorolac exerts typical NSAID effects. It prolongs the bleeding time and can impair renal function, especially in a patient
with preexisting renal disease. Its primary use is as a parenteral
agent for pain management, especially for treatment of postoperative patients. The answer is D.
6. In overdose, acetaminophen causes fulminant liver failure as a
result of its conversion by hepatic cytochrome P450 enzymes
to a highly reactive metabolite. The answer is C.
7. At doses needed to treat acute gout, colchicine frequently
causes significant diarrhea. Such gastrointestinal effects are
less likely with the lower doses used in chronic gout. The
answer is D.
8. Allopurinol is the only drug listed that decreases production of uric acid. Probenecid increases uric acid excretion.
Colchicine and hydroxychloroquine do not affect uric acid
metabolism. Aspirin actually slows renal secretion of uric acid
and raises uric acid blood levels. It should not be used in gout.
The answer is A.
9. Celecoxib is a COX-2-selective inhibitor. Although the
COX-2 inhibitors have the advantage over nonselective
NSAIDs of reduced gastrointestinal toxicity, clinical data
suggest that they are more likely to cause arterial thrombotic
events. A history of myocardial infarction would be a compelling reason to avoid a COX-2 inhibitor. The answer is C.
10. Etanercept is a recombinant protein that binds to tumor
necrosis factor and prevents its inflammatory effects. The
answer is B.

CHAPTER 36 NSAIDs, Acetaminophen, &Drugs Used in Rheumatoid Arthritis &Gout

325

SKILL KEEPER ANSWERS: OPIOIDS

(SEE CHAPTER 31)
1. Morphine is the prototype strong opioid. Fentanyl is a
strong agent with a rapid onset that is commonly used
in the hospital. Methadone is a strong agonist used in
maintenance programs for patients addicted to opioids.
Codeine, oxycodone, and hydrocodone are moderate
agonists, whereas propoxyphene is a weak agonist.
2. Constipation and sedation occur with therapeutic doses;
constipation should be managed with stool softeners. In
overdose, opioids cause a triad of pinpoint pupils, coma,
and respiratory depression.
3. Naloxone, a nonselective opioid receptor antagonist, is an
antidote for opioid overdose.

Therapy of Selected Diseases

Genetic disposition
Environmental factors
Infection
trauma

Acute trigger

Immune system: reaction against articular tissue

Synovitis

Pain

CHECKLIST
Prostaglandins

When you complete this chapter, you should be able to:

Chemotactic
factors

Inflammation

Permeability

Describe the effects of NSAIDs on prostaglandin synthesis.

Contrast the functions of COX-1 and COX-2.
Compare the actions and toxicity of aspirin, the older nonselective NSAIDs, and the

Bone
destruction

COX-2-selective drugs.
from the market.

Phospholipases

Describe the toxic effects of aspirin.

Describe the effects and the major toxicity of acetaminophen.
Name 5 disease-modifying antirheumatic drugs (DMARDs) and describe their

toxicity.

Contrast the pharmacologic treatment of acute and chronic gout.

Describe the mechanisms of action and toxicity of 3 different drug groups used in

gout.

Cartilage
destruction

Collagenases

Explain why several of the highly selective COX-2 inhibitors have been withdrawn

Peptidases

IL-1

Inflammation

TNF
Side effects:
Pneumonitis, nausea,
vomiting, myelosuppression

Non-steroidal
anti-inflammatory
drugs
(NSAIDs)

Methotrexate, p.o. /s.c.

weekly dosing
Sulfasalazine p.o.

allergic reaction, nephrotoxicity,

gastrointestinal disturbances

Glucocorticoids

Gold parenteral

Lesions of mucous membranes,

kidney, skin, blood dyscrasias

Relief of symptoms
Remission

Discontinuation because of:

side effects
or
insufficient efficacy

3
4
Months

6
Years

A. Rheumatoid arthritis and its treatment

Lllmann, Color Atlas of Pharmacology 2000 Thieme

All rights reserved. Usage subject to terms and conditions of license.

321

PART VI Drugs with Important Actions on Blood, Inflammation, & Gout

Reversible inhibition
of COX-1 and COX-2
results in decreased
prostaglandin synthesis

Acetylation of COX-1
and COX-2 results in
decreased prostaglandin
synthesis

Mechanism
of Action

Analgesia, antipyretic,
and anti-inflammatory
closure of patent
ductus arteriosus

Analgesia, antipyretic,
anti-inflammatory,
and antithrombotic
prevention of colon
cancer

Clinical
Applications

Rapid metabolism and

renal elimination

Duration of activity
islonger than
pharmacokinetic
half-life of drug due
to irreversible COX
inhibition

Pharmacokinetics

GI toxicity, nephrotoxicity
hypersensitivity due to increased
leukotrienes interference with aspirins
antithrombotic action

Gastrointestinal (GI) toxicity,

nephrotoxicity, and increased bleeding
time at therapeutic levels
hypersensitivity reaction due to
increased leukotrienes tinnitus,
hyperventilation metabolic acidosis,
hyperthermia, coma in overdose

Toxicities, Drug Interactions

Mechanism unknown,
weak COX inhibitor

Selective, reversible
inhibition of COX-2
results in decreased
prostaglandin synthesis

Analgesia, antipyretic

Analgesia, antipyretic,
and anti-inflammatory

Cytotoxic to rapidly
dividing immune cells
due to inhibition of
dihydrofolate reductase

Anticancer, rheumatic
disorders

Inhibition of renal reuptake

of uric acid

Inhibition of microtubule
assembly decreases macrophage migration and
phagocytosis

Active metabolite
irreversibly inhibits
xanthine oxidase and
lowers production of
uricacid
Febuxostat: reversible inhibitor of xanthine oxidase

Allopurinol

Xanthine oxidase inhibitors

Sulfinpyrazone: similar to probenecid

Probenecid

Uricosurics

Colchicine

Microtubule assembly inhibitor

Chronic
gout, adjunct
to cancer
chemotherapy

Chronic gout,
prolongation of
antimicrobial
drug action

Chronic and
acute gout,
familial
Mediterranean
fever

Diverse array of DMARDs available for clinical use. See Table 36-2

Methotrexate

Disease-modifying antirheumatic drugs (DMARDs)

Acetaminophen

Other analgesic

Celecoxib

COX-2 inhibitor

Activated by xanthine
oxidase oral drug

Oral drug

Oral drug

Renal elimination

Hepatic conjugation

Hepatic metabolism

GI upset, hypersensitivity reactions, bone

marrow suppression

Exacerbation of acute gout,

hypersensitivity reactions, inhibits renal
tubular secretion of weak acids such as
methotrexate

Diarrhea, severe liver and kidney damage

in overdose

Nausea, mucosal ulcers, hematotoxicity,

hepatotoxicity, teratogenicity

Hepatotoxicity in overdose (antidote is

acetylcysteine) hepatotoxicity more
likely with chronic alcohol consumption

Nephrotoxicity hypersensitivity due

to increased leukotrienes less risk of
GI toxicity than nonselective NSAIDs
greater risk of thrombosis than
nonselective NSAIDs

Many nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) available for clinical use. See Table 36-1

Ibuprofen

Nonselective NSAIDs

Aspirin

Salicylates

Subclass

DRUG SUMMARY TABLE: NSAIDs, Acetaminophen, & Drugs for Rheumatoid Arthritis
& Gout

326